The present invention concerns 8-D-homoarginine vasopressin analogues.
In many laboratories great attention has been paid to the preparation of derivatives-of arginine vasopressin wherein the arginine at the 8-position is replaced with D-homoarginine and the tyrosine at the 2-position is replaced with non-natural amino acids (Zaoral et al.: Collection of Czech. Chem. Commun., 31, 310, 1966; 31, 90, 1966; 32, 1250, 1967; 35, 1716, 1970; 37, 3350, 1972; 40, 905, 1975; 41, 2088, 1976; Huguenin and Boissonnas: Helv. Chim. Acta, 46, 1669, 1963; Lindeberg et al: J. Med. Chem., 15, 629, 1972; 17, 781, 1974; Lindeberg: Int. J. Peptide Prot. Res., 7, 395, 1975; Lindeberg et al.: Int. J. Peptide Prot. Res., 8, 193, 1976; Bodanszky and Lindeberg: J. Med. Chem., 14, 1197, 1971). The published results reflect modifications of some biological effects (e.g. pressoric and antidiuretic) depending on the replacement of the L-amino acid with the D-form, as well as on the shift in the position of the positively charged functional group and on the nature of the amino acid group at the 8-position of the peptide chain. This shift in the L-form of the substituent influences the accessibility of the peptide bond formed by the basic amino acid carboxyl group to trypsin cleavage (Dimeli and Barth: Collection of Czech. Chem. Commun., 44, 2451, 1979).
Increasing the distance of the guanidine group in the vasopressin (homoarginine) line retains the antidiuretic activity at almost an unchanged level (Lindeberg et al.: J. Med. Chem., 17, 781, 1974). In deamino analogues one encounters a relative decrease in antidiuretic activity (Lindeberg et al.: J. Med. Chem., 17, 781, 1974; Skopkova et al.: Collection of Czech. Chem. Commun., 46, 1850, 1981).
The replacement of L-homoarginine with its D-form in deamino analogues (Zaoral and Brtnik: Collection of Czech. Chem. Commun., 40,905, 1975) enhances the decrease in the antidiuretic effect by more than one order of magnitude (Skopkova et al.: Collection of Czech. Chem. Commun., 46, 1850, 1981).
The combined replacement of amino acid residues at both the 2- and 8-positions of the 8-L-arginine vasopressin peptide chain represents one of the most potent approaches to qualitative, as well as quantitative, alterations in the biological properties of this type of peptide (K. Jost et al.: Handbook of Neurohypophysial Hormone Analogues, CRC Press, Boca Raton, U.S.A., 1987). A possibility for further alterations is offered by the free amino group of cysteine at the 1-position of the peptide, especially from the standpoint of prolonged action.